By combined use of immunochemistry, spin-label EPR spectroscopy, and electron microscopy it is proposed to investigate the molecular events that occur during complement induced lysis of cells. Most, if not all, functions of complement are oriented toward membranes, however, the detailed mode of action of complement on membranes remains to be elucidated. The use of single-bilayer lipid vesicles as membrane models for complement attack allows us to study the primary events during cell lysis undisturbed by secondary reactions. By incorporating spin-labels into lipid vesicles information concerning the interaction between lipid membranes and complement proteins will be obtained. In addition, labeling of individual complement proteins allows one to estimate the extent of penetration of the complement complex into the lipid phase. The approximate extent of the penetration will also be studied by freeze-fracture electron microscopy in order to obtain independent results. High-resolution electron microscopy should also help us to determine the molecular shape of the complex after its removal from the lipid membrane. Using lipids of different chemical composition as well as activating the attack mechanism through the properdin pathway (thus avoiding the prior presence of immune complexes), we hope to find out whether specific membrane receptors are necessary for complement attack. The studies performed with model lipid membranes will be repeated whenever possible on erythrocytes to verify that the conclusions drawn from the model studies are applicable to natural membranes. A fuller understanding of the role of complement in the body's immune defense system will undoubtedly open the way to new and better means of controlling infections, allergic disorders and autoimmune diseases.